This proposal describes a 5 year training program for the development of an academic career in lung cancer research. The applicant completed a structured Pulmonary and Critical Care fellowship at the University of Colorado Denver in 2010, and will now expand his scientific skills to develop into an independent investigator. This program will extend our knowledge of lung cancer progression and metastasis. Dr. Robert Keith will mentor the applicant's scientific development. Dr. Keith is an established researcher in the field of lung cancer, especially with regards to lung cancer chemoprevention. He is the Associate Chief of Staff for Research and Development at the Denver VA Medical Center. To enhance the training, the program will enlist the expertises of Dr. Raphael Nemenoff, Professor of Medicine and a recognized leader in the field of lung cancer research, especially with regards to the tumor microenvironment; and Dr. Mary Weiser-Evans, an Associate Professor of Medicine with extensive experience in developing in vivo animal models. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. Research will focus on the role of PPARy, which is a member of the nuclear receptor superfamily of ligand-activated transcription factors, in lung cancer progression and metastasis. Recent work in the laboratory of Dr. Nemenoff has shown that treating mice with pioglitazone, which is a pharmacological PPARy activator, accelerates lung cancer metastasis. Previous work from the Nemenoff laboratory and others has shown that activation of PPARy in cancer cells promotes differentiation and inhibits transformed growth. Thus, we hypothesize that treatment with pioglitazone leads to activation of PPARy in cells in the tumor microenvironment, such as tumor-associated macrophages, which accelerates lung cancer metastasis. The specific aims include: 1) determine the effect of systemic PPARy activation on lung cancer progression and metastasis, 2) assess the effect of selective deletion of PPARy in macrophages on metastasis, and 3) establish the role of macrophage-specific PPARy in mediating interactions between cancer cells and macrophages. If pioglitazone, which is a member of the thiazolidinedione class of antidiabetic agents, indeed accelerates metastasis, then there may be far-reaching implications for diabetics currently being prescribed thiazolidinediones. The Denver VA Medical Center and the Division of Pulmonary Sciences and Critical Care Medicine at the University of Colorado Denver provide an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the potential for the applicant to establish a scientific niche from which an academic career can be constructed.